Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted

Jun 19, 2018 - (1) It is well-known that the (most) nucleophilic positions of pyrene are the 1, 3, ... (11) In all of the aforementioned cases, the py...
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Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position Ana M. Dmytrejchuk, Sydney N. Jackson, Rolande Meudom, John D. Gorden, and Bradley L. Merner J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01491 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 22, 2018

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The Journal of Organic Chemistry

Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position. Ana M. Dmytrejchuk, Sydney N. Jackson, Rolande Meudom, John D. Gorden, and Bradley L. Merner* Department of Chemistry and Biochemistry, Auburn University, Auburn, AL, 36849, USA

ABSTRACT: The synthesis of 1,2,4,5, 1,2,9,10-tetrasubstituted, and 1,2,4,5,8-pentasubsutituted pyrenes has been achieved by initially functionalizing the K-region of pyrene. Bromination, acylation, and formylation reactions afford high to modest levels of regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5-dimethoxypyrene. Access to 4,5dimethoxypyren-1-ol and 9,10-dimethoxypyren-1-ol enabled, a rare, C-2 primary alkyl substitution of pyrene.

The substitution chemistry of pyrene can be highly predictable based on the nature of electrophilic reagents employed in an (electrophilic) aromatic substitution (EAS) reaction; however, controlling selectivity can be an issue.1 It is well known that the (most) nucleophilic positions of pyrene are the 1, 3 ,6, and 8-positions and in the presence of small or non-bulky electrophiles, substitution at these positions is generally afforded (Scheme 1A).2 While selective mono- and tetrasubstitution can be achieved, selective di and trisubstitution at these positions is virtually impossible. In fact, if a selectively di or trisubstituted pyrene is desired it must be prepared using a multistep synthetic sequence.3 Such indirect methods for forming selectively functionalized pyrenes requires the conversion of [2.2]metacyclophane derivatives into pyrene (Scheme 1B),4 partial reduction of pyrene (b ring hydrogenation) followed by EAS of the resulting 4,5,9,10-tetrahydropyrene,5 or cyclization reactions of appropriately substituted biphenyl derivatives (Scheme 1C).6 Substitution of the 2 or 2 and 7 positions directly can be accomplished by using large or bulky electrophilic reagents.1-3 Particularly, tert-butyl substitution at one of the a rings of pyrene will block or attenuate further substitution at the neighboring 1 and 3 positions, allowing for selective functionalization of nucleophilic carbons at the unsubstituted apical ring (6, 7, and 8-positions).7 Direct borylation of the 2 or 2 and 7 positions provides a means for subsequent CC bond formation that does not require quaternization of the alkyl electrophile (Scheme 1A).8 The 4, 5, 9, and 10 positions of pyrene, known as the K-region, are not as susceptible to EAS reactions and typically display alkene-like reactivity.5 This dichotomy in reactivity has enabled the synthesis of 1,4,5,8-,9 2,4,5,7-,10 and 4,5,9,10tetrasubstituted pyrene derivatives (Scheme 2A).11 In all of the aforementioned cases, the pyrene nucleus was subjected to difunctionalization reactions after the K-region was first substituted. Herein, a strategy for the regioselective substitution of the pyrene nucleus that involves monofunctionalization reac-

tions after initial substitution of the K-region (Scheme 2B) is reported. This strategy provides access to unsymmetrically A. Electrophilic aromatic substitution (EAS) of pyrene 2 E

3

1

a

E

E

10

4

b

bulky electrophiles

b

9

5

a 8

E = t-Bu, Bpin,

6 7

Me Cl

small electrophiles E = Br, CHO, C(O)Me, NO2

pyrene Me R non-K-region (1, 2, 3, 6, 7, & 8) susceptible to subst.; easier to control r.r. r.r. = regioisomer ratio

E

susceptible to subst.; difficult to control r.r.

B. Unsymmetrical pyrenes with primary C-2 alkylation R1

R1

R2 R1

OMe

I2 PhH, 60 °C

DDQ PhH

94%

73%

multistep synthesis R1 = Me; R2 = t-Bu

R2

R2

C. Symmetrical and unsymmetrical pyrenes via alkyne annulations R1

R1 R2

X

X

R3

R1 R2

R2

TFA then X TfOH

R2

X PtCl2 PhMe

52%

63%

R1=R3=t-Bu R2= H X=p-OMeC6H4

R1=OMe; R3=OBn R2=CH2NHBoc X=H

R3

R3

Scheme 1. EAS chemistry of pyrene and indirect synthesis of symmetrical and unsymmetrical pyrenes.

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substituted pyrene derivatives and sterically hindered or unhindered hydroxypyrene derivatives, which can be used for direct, primary C-allylation of the 2-position. The latter has been a longstanding challenge for pyrene-based chemical synthesis. The C-allyl unit provides a functional group handle from which two identical pyrene systems can be brought together by a metathesis reaction. Furthermore, a regioselectively functionalized 1,2,4,5,8-pentasubstituted pyrene derivative has been synthetized using sequential monofunctionalization reactions.

zyl (Bn) and 2-naphthyl (Nap) groups could be achieved,13 however, attempts to install bulky silyl groups proved to be limiting. Alkylation with both TBDPSCl and TIPSCl was sluggish and did not result in formation of the desired silyl ethers. Furthermore, isolation 4,5-dihydroxypyrene can be problematic and thus using the more reactive silyl triflate derivatives was not an option. Indeed, formylation of benzylated pyrene derivative 1b gave a 4:1 ratio of constitutional isomers, in favor of 2b (entry 4, Scheme 3). Unfortunately, 1b and 1c succumbed to dealkylation under Rieche, or Rieche and Vilsmeier-Haak formylation conditions, respectively (entries 3, 5, and 6, Scheme 3).

Scheme 2. Synthesis of tetrasubstituted pyrenes via K-region substitution. Selective substitution of the pyrene K-region can be achieved using a known method to afford 4,5dimethoxypyrene.12 While several groups have used 1a or related alkoxy pyrenes in the preparation of regioselectively functionalized pyrene derivatives,10-12 to the best of our knowledge, the successful incorporation of a single substituent or functional group (directly) at the 1-position of 1a has not been reported. Access to such a strategy would allow for preparation of unsymmetrically substituted pyrene derivatives, which have been limited using direct substitution methods. One of the most useful monofunctionalization reactions of pyrene is the Rieche formylation, and this reaction has been employed in the synthesis of several pyrene-1-carbaldehyde derivatives.7a,b,d Based on the precedent for 4,5dimethoxypyrene to undergo 1,8-dibromination, leaving the 3 and 6 positions untouched (Scheme 2A), we anticipated that only 4,5-dimethoxypyrene-1-carbaldehyde (2a) would be afforded upon treatment of 1a with dichloromethyl methyl ether in the presence of TiCl4. To our surprise, a 1.5:1 ratio of 2a and 9,10-dimethoxypyrene-1-carbaldehyde (3a) (effective substitution at the 3-position, see pyrene numbering in Scheme 1A) was produced. A Vilsmeier-Haack-type formylation of 1a produced a slight increase in regioselectivity (2:1 r.r., 2a:3a) and comparable yield of 75%. To attenuate formylation at the effective 3-postiton of 1a, larger substituents were placed at the 4 and 5 positions. The introduction of both ben-

Scheme 3. Synthesis of 1-hydroxypyrenes 4a and 5a Separation of the mixture of aldehydes afforded from both formylation protocols was possible, however, tedious chromatography was required (see Supporting Information). As such, this mixture (R = Me) was directly subjected to a Dakin oxidation reaction to afford an easily separable pair of 1-hydroxypyrenes 4a and 5a (Scheme 4). It should be noted that both 4a and 5a are soluble in CDCl3, however, the 1H NMR spectrum of 4a is poorly resolved in this solvent. The faster moving (Rf = 0.50, 1:4 EtOAc/hexanes) 1hydroxypyrene 5a gave a well-resolved 1H NMR spectrum in CDCl3 (see Supporting Information). Direct access of 4a could be achieved by following a slightly modified synthetic protocol. Treatment of 1a with AcCl and AlCl3 in dichloromethane at 0 °C afforded monoacylation product 6 in 87% yield. The conversion ketone 6 to 4a was not trivial and required several weeks of optimization. Standard Bayer-Villiger oxidation conditions using m-CBPA or related peroxy acids led to either poor yields of the desired acetate ester, or the formation of numerous unidentified by-products. Employing a boric acid-mediated protocol that had been reported by Harvey and co-workers for the synthesis of 1-hydroxypyrene,14 gave

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The Journal of Organic Chemistry the desired acetate ester, however, complete consumption of the ketone was not achieved, resulting in a low overall yield of 4a. Finally, it was discovered that clean conversion of 1a to 4a could be achieved by first oxidizing the methyl ketone to the corresponding acetate ester, in the presence of a catalytic amount of SeO2 and H2O2,15 followed by direct hydrolysis of the crude material to afford 4a in 5% overall yield.

Scheme 4. Synthesis of primary alkylated, tetrasubstituted pyrenes 10 and 14. At this juncture, hydroxypyrenes 4a and 5a were subjected to an identical five-step sequence, which centered on the installation of a primary C-allyl group at the 2-position. Upon O-allylation of 4a under standard conditions, 1-allyloxy4,5-dimethoxypyrene (7) was afforded in 87% yield (Scheme 4A). Heating 7 to 190 °C in N,N-diethylaniline for 6 hours brought about a Claisen rearrangement that produced 8 in 74% yield. Subjecting hydroxypyrene 5a to the same two-step sequence produced 12 in comparable yield, however, 11 proved

to be (moderately) susceptible to deallylation. Approximately 10% of 5a was produced in this reaction, along with 18% of unreacted starting material. The free alcohols of 8 and 12 were sulfonylated to give 9 and 13 in 89% and 51% yields, respectively. Olefin metathesis in the presence of Grubbs first-generation catalyst gave a 4.7:1 mixture of alkene diastereomers, in the case of 9, which were directly subjected to transfer hydrogenation using the Hoveyda-Grubbs secondgeneration catalyst to afford 10 in 55% overall yield. It should be noted that a one-pot metathesis, transfer hydrogenation sequence using only the Hoveyda-Grubbs second-generation catalyst,16 was attempted, however, a much lower yield of 10 was obtained. In the case of triflate 13, a 2.7:1 mixture of alkene diastereomers was produced when subjected to identical olefin metathesis conditions. Transfer hydrogenation of this mixture afforded 14 in 64% yield over two steps. Determination of the regiochemical outcome of the formylation reaction that produced both 2a and 3a (Scheme 3), was initially made on the basis of 1H NMR analysis. In particular, the major constitutional isomer displayed a doublet at 9.38 ppm, which is indicative of a K-region proton flanked by an aldehyde group at the 1-position of pyrene. The absence of this signal from the minor regioisomer produced in this reaction suggested 9,10-dimethoxypyren-1-carbaldehyde as its structure. Secondly, the assumption that only 1-acetyl-4,5dimethoxypyrene was afforded upon acylation of 1a with AcCl, and matching the NMR data of the hydrolysis product 4a with that obtained from the Dakin oxidation of 2a further supported the assignment of 2a and 4a. Nonetheless, a single crystal suitable for X-ray crystallographic analysis of 10 was obtained, allowing for the unambiguous assignment of the substitution pattern of the tetrasubstituted pyrenes synthesized (see Supporting Information, Figure SI-2). Access to triflated pyrenes such as 10 and 14, should enable the synthesis of arylated derivatives via cross-coupling reactions. Arylated pyrenes are of importance in the development of liquid crystalline and optoelectonic, pyrene-based materials.17 Furthermore, the bridging butyl and butenyl units can be subjected to benzylic and alyllic oxidation reactions to afford 1,4-diketones, which have been used in the synthesis of macrocyclic benzenoid systems.16a,18 With this in mind, the synthesis of a pentasubstituted pyrene 18, with both bromide

Scheme 5. Synthesis of 1,2,4,5,8-pentasubstituted pyrene 18. and triflate cross-coupling handles was pursued. Low temperature bromination of 1a, followed by acylation of the intermediate monobromide 15, furnished bromoketone 16 in 70% overall yield

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(Scheme 5). Subjecting 16 to the same reaction sequence as described above, gave 1,2,4,5,8-pentasubstituted pyrene 17 in 32% overall yield. Sulfonylation of the free alcohol in 17 afforded triflate 18 in 57% yield. The substitution pattern of 18, and the orthogonal nature of aryl bromides and triflates in cross-coupling and functional group interconversion reactions, will be of great use in the development of synthetic approaches to pi-extended macrocyclic systems, such as carbon nanobelts.

In conclusion, the regioselective synthesis of 1,2,4,5 and 1,2,9,10-tetrasubstituted pyrenes has been achieved using sequential monofunctionalization reactions of 4,5dimethoxypyrene. Formylation, followed by Dakin oxidation, of 4,5-dimethoxypyrene provides access to separable 1-hydroxypyrene derivatives (1,4,5 and 1,9,10 substituted), while acetylation, followed by Baeyer-Villiger oxidation to a single 1-hydroxy-4,5-dimethoxyprene. The 2 position of pyrene can be subsequently C-allylated a via Claisen rearrangement, which represents a rare example of direct, primary alkylation at the 2-position of pyrene. A 1,2,4,5,8pentasubstituted pyrene derivative 18, containing both bromide and triflate cross-coupling handles has been synthesized using sequential monofunctionalization reactions. Finally, olefin metathesis has enabled the synthesis of a 1,4-bis(1-pyrenyl)butane (and but-2-ene) derivatives 10 and 14. The conversion such compounds into 1,4diketones and their application pi-extended macrocycle synthesis is underway in our laboratory. The synthesis of these macrocycles will be reported in due course. EXPERIMENTAL SECTION General experimental conditions: All reactions were run in flame or oven-dried (120 °C) glassware and cooled under a positive pressure of ultra high pure nitrogen or argon gas. All chemicals were used as received from commercial sources, unless otherwise stated. Anhydrous reaction solvents were purified and dried by passing HPLC grade solvents through activated columns of alumina (Glass Contour SDS). All solvents used for chromatographic separations were HPLC grade (hexanes, ethyl acetate and dichloromethane). Chromatographic separations were preformed using flash chromatography, as originally reported by Still and co-workers, on silica gel 60 (particle size 43-60 µm), and all chromatography conditions have been reported as diameter × height in centimeters. Reaction progress was monitored by thin layer chromatography (TLC), on glass-backed silica gel plates (pH = 7.0). TLC plates were visualized using a handheld UV lamp (254 nm or 365 nm) and stained using an aqueous ceric ammonium molybdate (CAM) solution. Plates were dipped, wiped clean, and heated from the back. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded at 400 or 600 MHz, calibrated using residual undeuterated solvent as an internal reference (CHCl3, δ 7.27 and 77.2 ppm), reported in parts per million relative to trimethylsilane (TMS, δ 0.00 ppm), and presented as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets, ddt = doublet of doublet of triplets, bs = broad singlet, m = multiplet), coupling constants (J, Hz), and integration. High-resolution mass spectrometric (HRMS) data were obtained using a quadrupole time-of-flight (Q-TOF) spectrometer and electrospray ionization (ESI).

4,5-Dibenzyloxypyrene (1b): Sodium dithionite (0.56 g, 3.2 mmol) and tetrabutylammonium bromide (0.11 g, 0.32 mmol) were added to a stirred solution of pyrene-4,5-dione (0.25 g, 1.1 mmol) in THF (10 mL) and H2O (10 mL) at room temperature. After 15 min., a solution of NaOH (0.52 g, 13 mmol) in water (10 mL) was added to the reaction mixture followed by benzyl bromide (0.94 g, 5.4 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was diluted with EtOAc (20 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with H2O (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 18 cm, 50% dichloromethane/hexanes) to afford 1b as a light brown solid (0.064 g, 33%) and compound 21 (0.19 g, 54%): Rf = 0.21 (60% dichloromethane/hexanes). Compound 21 (0.19 g, 0.60 mmol) was re-subjected to the alkylation conditions described above to afford 1b (0.098 g, 39%): Rf = 0.82 (60% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 7.8 Hz, 2H), 8.18 (d, J = 7.7, Hz, 2H), 8.09 (s, 2H), 8.07 – 8.01 (m, 2H), 7.64 (d, J = 7.4 Hz, 4H), 7.47 – 7.44 (m, 4H), 7.42 – 7.38 (m, 2H), 5.43 (s, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 144.3, 137.6, 131.1, 128.7, 128.52, 128.50, 128.3, 127.4, 126.1, 124.7, 123.0, 119.7, 75.6; HRMS (ESI) calculated for C30H23O2 ([M+H]+) m/z = 415.1698, found 415.1701. 4,5-Bis(2-naphthyloxy)pyrene (1c): Sodium dithionite (0.34 g, 1.9 mmol) and tetrabutylammonium bromide (0.065 g, 0.19 mmol) were added to a stirred solution of pyrene-4,5-dione (0.14 g, 0.59 mmol) in THF (7 mL) and H2O (7 mL) at room temperature. After 15 min., a solution of KOH (0.27 g, 4.8 mmol) in water (10 mL) was added to the reaction mixture, followed by 2-(bromomethyl)naphthalene (0.69 g, 3.1 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was diluted with EtOAc (20 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with H2O (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 18 cm, 70% dichloromethane/hexanes) to afford 1c as a white solid (0.050 g, 17%) and compound 22 (0.020 g, 9%): Rf = 0.28 (60% dichloromethane/hexanes). Compound 22 (0.020 g, 0.053 mmol) was re-subjected to the alkylation conditions described above to afford 1c (0.010 g, 36%): Rf = 0.80 (60% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.65 (d, J = 7.8 Hz, 2H), 8.20 (d, J = 7.6 Hz, 2H), 8.11 (s, 2H), 8.10 – 8.05 (m, 4H), 7.94 – 7.90 (m, 4H), 7.81 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.57 – 7.51 (m, 4H), 5.61 (s, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 144.5, 135.1, 133.4, 133.2, 131.2, 128.6, 128.4, 128.2, 127.8, 127.5, 127.3, 126.30, 126.25, 126.20, 124.7, 123.1, 119.7, 75.9 (only 18 of 19 carbons observed); HRMS (ESI) calculated for C38H27O2 ([M+H]+) m/z = 515.2011, found 515.2015. 4,5-Dimethoxypyrene-1-carbaldehyde (2a) and 9,10dimethoxypyrene-1-carbaldehyde (3a): POCl3 (9.8 g, 64 mmol) was added dropwise to a stirred 0 °C solution of Nmethylformanilide (4.3 g, 32 mmol) in 1,2-dichlorobenzene (15 mL). After 10 min., the cooling bath was removed and a solution of 4,5-dimethoxypyrene (2.66 g, 10.1 mmol) in 1,2dichlorobenzene (10 mL) was added. The reaction was then

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The Journal of Organic Chemistry heated at 90 °C. After 48 h, the reaction mixture was poured into ice, neutralized with 1 M NaOH, and diluted with EtOAc (60 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 60 mL). The combined organic extracts were washed with brine (80 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5 cm × 15 cm; 80% dichloromethane/hexanes) to afford a mixture of 2a and 3a (2:1 r.r) as a yellow solid (2.2 g, 75%): Rf = 0.31 (80% dichloromethane/hexanes); a small portion of 2a was isolated from a single chromatography fraction and characterized: 1H NMR (600 MHz, CDCl3) δ 10.74 (s, 1H), 9.41 (d, J = 9.2 Hz, 1H), 8.60 (dd, J = 7.8, 1.1 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.25 (dd, J = 7.6, 1.1 Hz, 1H), 8.11 – 8.07 (m, 1H), 4.26 (s, 3H), 4.18 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 193.4, 147.8, 144.3, 133.4, 132.1, 131.2, 131.0, 130.6, 128.3, 127.1, 126.9, 126.6, 123.2, 122.9, 122.5, 121.7, 118.9, 61.6, 61.4; HRMS (ESI) calculated for the mixture of constitutional isomers C19H15O3 ([M+H]+) m/z = 291.1021, found 291.1057. 4,5-Dibenzyloxypyrene-1-carbaldehyde (2b) and 9,10dibenzyloxypyrene-1-carbaldehyde (3b): POCl3 (0.022 g, 0.14 mmol) was added dropwise to a stirred 0 °C solution of Nmethylformanilide (0.009 g, 0.07 mmol) in 1,2dichlorobenzene (0.6 mL). After 10 min., the cooling bath was removed and the temperature was increased to 80 °C. After 15 min., a solution of 1b (0.010 g, 0.024 mmol) in 1,2dichlorobenzene (0.3 mL) was added and the reaction was heated at 80 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), then poured into ice water (10 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (3 × 5 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 18 cm; 60% dichloromethane/hexanes) to afford an inseparable mixture of constitutional isomers 2b and 3b (3.8:1 r.r) as a yellow solid (0.0084 g, 84%): Rf = 0.36 (60% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 11.51 (s, 1H), 10.77 (s, 3H), 9.47 (d, J = 9.2 Hz, 4H), 8.66 (d, J = 7.8 Hz, 4H), 8.63 – 8.61 (m, 5H), 8.52 (d, J = 8.1 Hz, 1H), 8.46 (d, J = 8.1 Hz, 4H), 8.34 (d, J = 9.2 Hz, 4H), 8.30 (d, J = 7.6 Hz, 4H), 8.27 (d, J = 7.6 Hz, 1H), 8.23 – 8.18 (m, 3H), 8.13 – 8.08 (m, 7H), 7.63 – 7.60 (m, 18H), 7.50 – 7.48 (m, 3H), 7.47 – 7.43 (m, 19H), 7.42 – 7.38 (m, 10H), 5.53 (s, 2H), 5.49 (s, 7H), 5.41 (s, 7H), 5.29 (s, 2H); HRMS (ESI) calculated for the mixture of constitutional isomers C31H23O3 ([M+H]+) m/z = 443.1647, found 443.1642. 4,5-Dimethoxypyren-1-ol (4a): Concentrated H2S2O4 (5 drops) and a 35% solution (w/w) of hydrogen peroxide in water (5 drops) were added to a stirred solution of 2a and 3a (2:1 r.r, 0.212 g, 0.731 mmol) in 1:1 methanol/dichloromethane (8 mL) at room temperature. After 4 h, the reaction mixture was poured into water (50 mL), the layers were separated, and the aqueous phase was extracted with dichloromethane (3 × 35 mL). The combined organic extracts were sequentially washed with water (2 × 30 mL), a saturated solution of NaHCO3 (60 mL) and brine (60 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 18 cm; 10% EtOAc/hexanes) to afford 4a as a brown solid (0.11 g, 52%):

Rf = 0.20 (20% EtOAc/hexanes); 1H NMR (400 MHz, CD3OD) δ 8.35 (d, J = 9.1 Hz, 1H), 8.29 – 8.23 (m, 2H), 7.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.94 – 7.87 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 4.14 (s, 3H), 4.09 (s, 3H); 13C{1H}NMR (101 MHz, CD3OD) δ 151.7, 145.0, 142.0, 131.8, 128.8, 125.7, 125.1, 124.2, 123.01, 122.91, 121.04, 120.70, 119.92, 118.80, 117.78, 112.4, 60.1, 59.9; HRMS (ESI) calculated for C18H15O3 ([M+H]+) m/z = 279.1021, found 279.1009. 9,10-Dimethoxypyren-1-ol (5a): isolated as a yellow solid (0.058 g, 29%): Rf = 0.50 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 8.30 (dd, J = 7.7, 1.2 Hz, 1H), 8.07 – 8.00 (m, 2H), 7.99 – 7.93 (m, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.29 (s, 3H), 4.14 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 153.2, 145.6, 143.9, 132.2, 128.7, 127.7, 126.9, 126.5, 124.7, 124.6, 124.5, 124.3, 124.0, 117.7, 115.3, 112.7, 62.1, 61.1; HRMS (ESI) calculated for C18H15O3 ([M+H]+) m/z = 279.1021, found 279.1021. 1-(4,5-Dimethoxypyren-1-yl)ethanone (6): Acetyl chloride (0.065 g, 0.84 mmol) was added to a stirred 0 °C solution of AlCl3 (0.25 g, 1.7 mmol) and 4,5-dimethoxypyrene (0.20 g, 0.76 mmol) in dichloromethane (8 mL). After 15 min., the reaction mixture was poured into ice water (10 mL), the layers were separated, and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with a saturated solution of NaHCO3 (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 15 cm, dichloromethane) to afford 6 as a bright yellow solid (0.20 g, 87%): Rf = 0.12 (80% dichloromethane/hexane); 1H NMR (600 MHz, CDCl3) δ 9.09 (d, J = 9.3 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.25 – 8.18 (m, 2H), 8.11 – 8.06 (m, 1H), 4.26 (s, 3H), 4.21 (s, 3H), 2.92 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 202.3, 146.7, 144.2, 131.8, 131.5, 130.6, 129.9, 129.7, 128.4, 127.7, 126.7, 125.8, 125.1, 123.3, 122.7, 120.9, 118.3, 61.5, 61.4, 30.7; HRMS (ESI) calculated for 6 C20H17O3 ([M+H]+) m/z = 305.1178, found 305.1190. Alternative synthesis of 4,5-dimethoxypyren-1-ol (4a): SeO2 (0.001 g, 0.001 mmol) and a 30% solution (w/w) of hydrogen peroxide in water (0.13 mL, 1.1 mmol) were added to a stirred 50 °C solution of 6 (0.086 g, 0.28 mmol) in t-BuOH (3 mL). After 4 h, the reaction mixture was cooled to room temperature, poured into water (30 mL) and further diluted with dichloromethane (15 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (3 × 15 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 23 as a light brown solid: Rf = 0.45 (dichloromethane); 1H NMR (400 MHz, CDCl3) δ 8.63 – 8.39 (m, 2H), 8.16 (d, J = 7.7, 1H), 8.13 – 8.07 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 4.23 (s, 3H), 4.22 (s, 3H) 2.58 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 170.0, 144.7, 144.6, 144.1, 130.9, 128.6, 128.1, 126.7, 126.5, 124.8, 123.8, 123.1, 122.7, 120.1, 119.91, 119.86, 119.6, 61.2, 21.2; HRMS (ESI) calculated for C20H17O4 ([M+H]+) m/z = 321.1127, found 321.1111. Potassium carbonate (0.64 g, 4.6 mmol) was added to a stirred solution of 23 in MeOH (20 mL) at room temperature. After 30 min., the reaction mixture was poured into ice water (10 mL)

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

and neutralized with 1 M HCl (10 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with a saturated solution of NaHCO3 (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 cm × 15 cm, dichloromethane) to afford 4a as a light yellow solid (0.042 g, 54% overall). 1-Allyloxy-4,5-dimethoxypyrene (7): K2CO3 (0.126 g, 0.912 mmol) and allyl bromide (0.11 g, 0.91 mmol) were added to a stirred solution of 4a (0.168 g, 0.603 mmol) in DMF (13 mL) at room temperature. After 2 h, the reaction mixture was poured into water (100 mL) and further diluted with 1 M HCl (50 mL). The resulting mixture was extracted with EtOAc (5 × 20 mL), the combined organic extracts were washed with 1 M HCl (3 × 30 mL) and a saturated solution of NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 cm × 15 cm; 50% dichloromethane/hexanes) to afford 7 as a yellow solid (0.15 g, 87%): Rf = 0.39 (50% dichloromethane/hexanes ); 1H NMR (600 MHz, CDCl3) δ 8.53 (d, J = 9.1 Hz, 1H), 8.46 – 8.39 (m, 2H), 8.11 (d, J = 7.6 Hz, 1H), 8.08 – 8.00 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 6.27 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.62 (dd, J = 17.3, 1.6 Hz, 1H), 5.42 (dd, J = 10.6, 1.5 Hz, 1H), 4.94 – 4.85 (m, 2H), 4.26 (s, 3H), 4.22 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 152.6, 145.1, 143.0, 133.5, 131.8, 129.2, 126.5, 126.4, 124.3, 123.9, 123.2, 122.3, 121.4, 120.8, 120.1, 118.9, 117.8, 109.7, 69.9, 61.3, 61.2; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z = 319.1334, found 319.1348. 4,5-Dimethoxy-2-(2-propen-1-yl)pyren-1-ol (8): Compound 7 (0.105 g, 0.331 mmol) was dissolved in N,N-diethylaniline (0.2 mL) and heated to 190 °C. After 12 h, the solvent was evaporated under a gentle stream of nitrogen and the residue was purified by flash chromatography (1.3 × 15 cm; 10% EtOAc/hexanes) to afford 8 as an off-white solid (0.078 g, 74%): Rf = 0.27 (10% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.47 – 8.21 (m, 3H), 8.16 – 7.89 (m, 3H), 6.22 (ddt, J = 16.6, 10.1, 6.2 Hz, 1H), 5.94 – 5.89 (m, 1H), 5.39 – 5.29 (m, 2H), 4.24 (s, 3H), 4.19 (s, 3H), 3.89 (bs, 2H); 13 C{1H}NMR (151 MHz, CDCl3) δ 148.8, 145.0, 143.1, 136.4, 131.42, 128.9, 126.7, 126.3, 123.9, 123.5, 123.1, 122.7, 122.2, 121.4, 120.8, 119.6, 118.9, 117.7, 61.4, 61.2, 37.0; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z = 319.1334, found 319.1336. 1-(Trifluorometanesulfonyl)oxy-4,5-dimethoxy-2-(2-propen-1yl)pyrene (9): Triflic anhydride (0.14 g, 0.35 mmol) and pyridine (0.03 g, 0.3 mmol) were added to a stirred 0 °C solution of 8 (0.056 g, 0.18 mmol) in dichloromethane (3.5 mL). The cooling bath was removed and 10 min. later the reaction mixture was poured into 1 M HCl (30 mL). The resulting mixture was extracted with dichloromethane (3 × 15 mL), the combined organic extracts were washed with and brine (35 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 12 cm; 20% dichloromethane/hexanes) to afford 9 as a yellow solid (0.071 g, 89%): Rf = 0.32 (20% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 7.8, 1.1 Hz, 1H), 8.41 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.22 – 8.15 (m, 2H), 8.10 – 8.02 (m, 1H), 6.17 (ddt, J = 16.1, 10.6,

6.6 Hz, 1H), 5.33 – 5.26 (m, 2H), 4.23 – 4.21 (m, 6H), 4.00 (d, 2H); 13C{1H}NMR (151 MHz, CDCl3) δ 145.8, 144.1, 140.1, 135.5, 131.4, 130.5, 129.7, 128.55, 128.52, 126.9, 125.7, 124.7, 122.9, 122.2, 121.3, 120.9, 120.1, 119.0 (JC-F = 318 Hz), 117.8, 61.41, 61.39, 35.4; HRMS (ESI) calculated for C22H16O5F3S ([M-H]−) m/z = 449.0676, found 449.0667. 1,4-Bis(1-(trifluorometanesulfonyl)oxy-4,5-dimethoxypyren-2yl)butane (10): Hoveyda-Grubbs second-generation catalyst (0.010 g, 0.016 mmol) and NaBH4 (0.025 g, 0.66 mmol) were added to stirred solution of 19 (0.110 g, 0.126 mmol) in 1:9 methanol/dichloromethane (14 mL). After 2 h, the reaction mixture was poured into water (30 mL) and further diluted with 1 M HCl (15 mL). The resulting mixture was extracted with dichloromethane (3 × 10 mL), and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 15 cm; 40% dichloromethane/hexanes) to afford 10 as an off-white solid (0.070 g, 70% BORSM, 0.010 g of 19): Rf = 0.21 (40% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.55 (d, J = 7.9, 1.1 Hz, 2H), 8.40 (s, 2H), 8.26 (d, J = 9.2 Hz, 2H), 8.23 – 8.17 (m, 4H), 8.13 – 8.07 (m, 2H), 4.22 (s, 6H), 4.19 (s, 6H), 3.32 (t, 4H), 2.12 – 2.02 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 148.1, 142.9, 140.1, 133.6, 130.7, 130.6, 128.6, 127.8, 126.6, 126.4, 126.0, 125.7, 123.0, 122.2, 121.2, 120.3, 117.9 (JC-F = 318 Hz), 61.7, 60.8, 30.5, 30.2; HRMS (ESI) calculated for C42H33O10F6S2 ([M+H]+) m/z = 875.1419, found 875.1459. 1-Allyloxy-9,10-dimethoxypyrene (11): K2CO3 (0.091 g, 0.66 mmol) and allyl bromide (0.08 g, 0.7 mmol) were added to a stirred solution of 5a (0.061 g, 0.22 mmol) in DMF (7 mL) at room temperature. After 20 h, the reaction mixture was poured into water (20 mL) and further diluted with 1 M HCl (25 mL). The resulting mixture was extracted with diethyl ether (3 × 15 mL), the combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 15 cm; 40% dichloromethane/hexanes) to afford 11 as a light brown solid (0.045 g, 98%): Rf = 0.22 (40% dichloromethane/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 7.5 Hz, 1H), 8.11 – 7.85 (m, 5H), 7.60 (d, J = 8.5 Hz, 1H), 6.40 – 6.23 (m, 1H), 5.62 (d, J = 17.2 Hz, 1H), 5.41 (d, J = 10.1 Hz, 1H), 4.89 (d, J = 5.6 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 153.6, 146.9, 146.3, 133.7, 132.0, 128.8, 127.6, 126.5, 126.0, 125.8, 125.39, 125.35, 124.2, 123.6, 118.4, 118.1, 118.0, 112.7, 71.4, 70.0, 61.5; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z = 319.1334, found 319.1324. 9,10-Dimethoxy-2-(2-Propen-1-yl)pyren-1-ol (12): Compound 11 (0.229 g, 0.719 mmol) was dissolved in N,Ndiethylaniline (0.3 mL) and heated to 190 °C. After 9 h, the solvent was evaporated under a gentle stream of nitrogen and the residue was purified by flash chromatography (1.3 × 15 cm; 40% dichloromethane/hexanes) to afford 12 as a dark yellow solid (0.13 g, 62% BORSM, 0.022 g recovered of 11 and 0.041 g of 5a): Rf = 0.35 (40% dichloromethane/hexanes); 1 H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.98 – 7.88 (m, 3H), 7.84 (d, J = 8.8 Hz, 1H), 6.24 (ddt, J = 16.7, 10.1, 6.5 Hz, 1H), 5.24 – 5.13 (m, 2H), 4.30 (s, 3H), 4.14 (s, 3H), 3.81 (d, J = 6.4 Hz,

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The Journal of Organic Chemistry 2H); 13C{1H}NMR (101 MHz, CDCl3) δ 151.1, 145.7, 144.1, 137.1, 131.9, 128.5, 127.5, 127.4, 126.17, 126.14, 124.5, 124.4, 124.2, 123.9, 123.5, 117.7, 116.0, 112.4, 62.2, 61.2, 34.8; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z = 319.1334, found 319.1319. 1-(Trifluorometanesulfonyl)oxy-2-(2-Propen-1-yl)-9,10dimethoxypyrene (13): Triflic anhydride (0.22 g, 0.60 mmol) was added to a stirred 0 °C solution of 12 (0.064 g, 0.20 mmol) in pyridine (2 mL). The cooling bath was removed and the temperature increased to 40 °C. After 4 h, the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), and poured into 1 M HCl (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 15 mL), the combined organic extracts were washed with 1 M HCl (20 mL), a saturated solution of NaHCO3 (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 15 cm; 20% dichloromethane/hexanes) to afford 13 as a light yellow solid (0.046 g, 51%): Rf = 0.23 (20% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.10 – 8.01 (m, 3H), 7.99 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.12 – 6.08 (m, 1H), 5.37 – 5.25 (m, 2H), 4.32 (s, 3H), 3.99 (s, 3H), 3.95 (d, J = 7.0 Hz, 2H); 13C{1H}NMR (151 MHz, CDCl3) δ 148.4, 143.2, 140.1, 135.7, 131.6, 131.0, 130.8, 128.8, 128.1, 126.8, 126.7, 126.3, 126.1, 123.4, 122.3, 121.4, 120.5, 119.1 (JC-F = 317 Hz), 118.0, 61.9, 61.1, 34.6; HRMS (ESI) calculated for C22H18O5F3S ([M+H]+) m/z = 451.0827, found 451.0825.

The residue was dissolved in dichloromethane (10 mL) and cooled to 0 °C, followed by addition of acetyl chloride (0.031 g, 0.42 mmol) and AlCl3 (0.14 g, 0.83 mmol). After 30 min., the reaction mixture was directly poured into ice water (20 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1.3 × 18 cm; 50% dichloromethane/hexanes) to afford 16 as a bright yellow solid (0.10 g, 70%): Rf = 0.29 (60% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 9.09 (d, J = 9.6 Hz, 1H), 8.51 – 8.45 (m, 2H), 8.41 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 4.24 (s, 3H), 4.19 (s, 3H), 2.91 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 201.9, 146.1, 143.9, 131.7, 131.4, 130.6, 129.3, 128.8, 128.08, 128.01, 127.8, 126.4, 123.6, 122.4, 121.2, 120.9, 118.8, 61.4, 61.2, 30.5; HRMS (ESI) calculated for C20H16BrO3 ([M+H]+) m/z = 383.0283, found 383.0276. 8-Bromo-4,5-dimethoxy-2-(2-propen-1-yl)pyren-1-ol (17): Compound 26 (0.29 g, 0.74 mmol) was dissolved in N,Ndiethylaniline (2 mL) and heated to 190 °C. After 48 h, the solvent was evaporated under a gentle stream of nitrogen and the residue was purified by flash chromatography (2.5 × 18 cm; 50% dichloromethane/hexanes) to afford 17 as an offwhite solid (0.21 g, 74%): Rf = 0.33 (50% dichloromethane/hexanes); HRMS (ESI) calculated for C21H17BrO3 ([M]+) m/z = 396.0361, found 396.0365. The 1H and 13C NMR spectra for 17 were poorly resolved. As such, it was subjected to triflation and characterized at a later stage – see below.

1,4-Bis(1-(trifluorometanesulfonyl)oxy-9,10-dimethoxypyren2-yl)butane (14): 14: Hoveyda-Grubbs second-generation catalyst (0.0005 g, 0.0009 mmol) and NaBH4 (0.006 g, 0.1 mmol) were added to stirred solution of 20 (0.025 g, 0.029 mmol) in 1:9 methanol/dichloromethane (1.5 mL). After 2 h, the reaction mixture was poured into water (25 mL) and diluted with 1 M HCl (15 mL). The resulting mixture was extracted with dichloromethane (3 × 12 mL), the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0.5 × 10 cm; 40% dichloromethane/hexanes) to afford 14 as an off-white solid (0.012 g, 95%): Rf = 0.30 (40% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 7.8, 1.2 Hz, 2H), 8.17 (d, J = 8.0, 7.6 Hz, 2H), 8.08 – 8.02 (m, 4H), 7.99 (s, 2H), 7.91 (d, J = 8.9 Hz, 2H), 4.29 (s, 6H), 3.90 (s, 6H), 3.26 (t, J = 6.8 Hz, 4H), 2.10 – 1.94 (m, 4H); 13C{1H}NMR (151 MHz, CDCl3) δ 148.1, 142.9, 140.1, 133.6, 130.7, 130.6, 128.6, 127.8, 126.6, 126.4, 126.0, 125.7, 123.0, 122.2, 121.2, 120.3, 118.9 (JC-F = 317 Hz), 61.7, 60.8, 30.5, 30.2, 29.7; HRMS (ESI) calculated for C42H32O10F6S2Na ([M+Na]) m/z = 897.1239, found 897.1194.

Triflate 18: Trifluoromethanesulfonic anhydride (0.03 g, 0.1 mmol) and pyridine (0.01 g, 0.1 mmol) were added to a stirred 0 °C solution of 17 (0.021 g, 0.053 mmol) in dichloromethane (1.5 mL). After 10 min., the reaction mixture was diluted with dichloromethane (5 mL) and neutralized with 1 M HCl (10 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 7 mL). The combined organic extracts were washed with 1 M HCl (10 mL), NaHCO3 (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0.5 × 10 cm; dichloromethane) to afford 18 as a yellow solid (0.027 g, 57%): Rf = 0.78 (dichloromethane); 1H NMR (600 MHz, CDCl3) δ 8.58 (d, J = 9.4 Hz, 1H), 8.43 (s, 1H), 8.41 – 8.35 (m, 2H), 8.30 (d, J = 8.3 Hz, 1H), 6.13 (ddt, J = 16.7, 9.9, 6.7 Hz, 1H), 5.31 – 5.25 (m, 2H), 4.22 – 4.18 (m, 6H), 3.98 (d, J = 6.6 Hz, 2H); 13 C{1H}NMR (151 MHz, CDCl3) δ 145.3, 144.0, 140.1, 135.0, 132.1, 130.9, 128.9, 128.6, 128.2, 128.0, 124.5, 123.2, 122.1, 121.9, 121.6, 121.5, 120.7, 118.8 (JC-F = 253 Hz), 117.9, 61.32, 61.27, 35.2; HRMS (ESI) calculated for C22H17BrF3O5S ([M+H]+) m/z = 528.9932, found 528.9926.

1-(8-Bromo-4,5-dimethoxypyren-1-yl)ethanone (16): Bromine (0.06 g, 0.4 mmol) was added dropwise to a stirred –78 °C solution of 4,5-dimethoxypyrene (0.10 g, 0.38 mmol) in dichloromethane (20 mL). After 10 min., the reaction mixture was directly poured into an aqueous saturated solution of Na2SO3 (10 mL), and the resulting mixture was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure.

Alkene 19: Grubbs first-generation catalyst (0.001 g, 0.001 mmol) was added to a stirred 40 °C solution of 9 (0.020 g, 0.043 mmol) in dichloromethane (0.8 mL). After 12 h, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (1.3 × 10 cm; 30% dichloromethane/hexanes) to afford 19 (dark yellow solid, 0.014 g, 78%, 4.7:1 d.r) as an inseparable mixture of diastereomers: Rf = 0.27 (35% dichloromethane/hexanes); 1H NMR (400

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MHz, CDCl3) δ 8.52 – 8.48 (m, 5H), 8.43 – 8.40 (m, 1H), 8.37 (s, 5H), 8.28 – 8.23 (m, 6H), 8.18 (d, J = 1.4 Hz, 5H), 8.16 (d, J = 1.1 Hz, 5H), 8.07 – 7.94 (m, 9H), 6.19 – 6.15 (m, 1H), 6.02 – 5.96 (m, 5H), 4.15 (s, 14H), 4.13 – 4.10 (m, 2H), 4.07 – 4.04 (m, 18H), 4.02 – 3.98 (m, 13H); 13C{1H}NMR (151 MHz, CDCl3) δ 145.8, 145.6, 144.1, 144.0, 140.1, 139.9, 131.8, 131.7, 130.5, 130.3, 130.2, 129.7, 129.42, 129.41, 128.62, 128.55, 128.43, 128.38, 127.0, 126.8, 125.7, 125.6, 124.7, 124.4, 122.9, 122.5, 122.2, 121.9, 121.3, 121.0, 120.80, 120.72, 120.2, 120.1, 119.8, 117.9, 61.4, 61.28, 61.25, 61.15, 34.4, 29.9, 29.1; HRMS (ESI) calculated for C42H31O10F6S2 ([M+H]+) m/z = 873.1263, found 873.1262. Alkene 20: Grubbs first-generation catalyst (0.003 g, 0.003 mmol) was added to a stirred 40 °C solution of 13 (0.047 g, 0.10 mmol) in dichloromethane (0.8 mL). After 12 h, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (1.3 × 15 cm; 30% dichloromethane/hexanes) to afford 20 (light yellow solid, 0.031 g, 67%, 2.7:1 d.r.) as an inseparable mixture of diastereomers: Rf = 0.38 (30% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3 δ 8.54 (d, J = 7.7 Hz, 4H), 8.20 (d, J = 7.5 Hz, 3H), 8.16 (d, J = 7.6 Hz, 1H), 8.12 – 8.04 (m, 10H), 7.99 (d, J = 9.0 Hz, 5H), 7.81 (d, J = 8.8 Hz, 1H), 6.12 – 6.08 (m, 1H), 6.02 – 5.97 (m, 3H), 4.32 – 4.27 (m, 12H), 4.18 – 4.14 (m, 2H), 4.04 – 3.98 (m, 6H), 3.95 (s, 3H), 3.89 (s, 9H); 13 C{1H}NMR (151 MHz, CDCl3) δ 148.44, 148.41, 143.1, 140.12, 140.09, 131.9, 131.0, 130.9, 130.8, 130.6, 129.6, 128.87, 128.80, 128.06, 128.04, 126.9, 126.71, 126.5, 126.26, 126.20, 126.18, 125.9, 123.4, 122.34, 122.29, 121.53, 121.46, 120.51, 120.50, 120.1, 118.0, 61.9, 61.02, 60.99, 33.6, 28.3; HRMS (ESI) calculated for C42H31O10F6S2 ([M+H]+) m/z = 873.1263, found 873.1257. 8-Bromo-4,5-dimethoxypyren-1-ol (25): SeO2 (0.009 g, 0.08 mmol) and a 30% solution (w/w) of hydrogen peroxide in water (1.0 mL, 12 mmol) were added to a stirred 50 °C solution of 6 (0.89 g, 2.9 mmol) in t-BuOH (12 mL). After 3 days, the reaction mixture was cooled to room temperature, poured into water (30 mL) and further diluted with dichloromethane (15 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (3 × 15 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 18 cm, 80% dichloromethane/hexane) to afford 24 (0.533 g, 57%): Rf = 0.48 (80% dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.53 (d, J = 8.5 Hz, 1H), 8.47 (d, J = 9.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 4.21 (s, 3H), 4.19 (s, 3H), 2.58 (s, 3H); 13 C{1H}NMR (151 MHz, CDCl3) δ 170.0, 144.7, 144.4, 144.2, 130.7, 129.4, 128.2, 126.8, 123.9, 123.2, 123.1, 121.8, 120.7, 120.5, 120.4, 119.8, 61.30, 61.27, 21.3; HRMS (ESI) calculated for 24 C20H16BrO4 ([M+H]+) m/z = 399.0232, found 399.0215. Compound 24 was dissolved in MeOH (20 mL) and K2CO3 (0.641 g, 4.64 mmol) was added, the resulting mixture was stirred for 30 min. The reaction mixture was directly poured into ice water (50 mL) and neutralized with 1 M HCl (40 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (3 × 30 mL). The combined organic extracts were washed with a saturated solu-

tion of NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 25 as a light brown solid (0.393 g, 82%): Rf = 0.24 (dichloromethane); HRMS (ESI) calculated for C18H13BrO3 ([M]+) m/z = 356.0048, found 356.0041. The 1H and 13C NMR spectra for 25 were poorly resolved. As such it was subjected to allylation and characterized at a later stage – see below. 1-Allyloxy-8-bromo-4,5-dimethoxypyrene (26): NaH (0.031 g, 1.3 mmol) and allyl bromide (0.17 g, 1.4 mmol) were added to a stirred solution of 25 (0.29 g, 0.82 mmol) in DMF (22 mL) at room temperature. After 30 min., the reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl (20 mL). The resulting mixture was extracted with dichloromethane (3 × 15 mL), the combined organic extracts were washed with water (40 mL) and a saturated solution of NaHCO3 (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (2.5 × 18 cm; dichloromethane) to afford 26 as a yellow solid (0.30 g, 91%): Rf = 0.70 (dichloromethane); 1 H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 9.4 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H), 8.38 (d, J = 9.4 Hz, 1H), 8.25 – 8.20 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H), 6.26 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.60 (dd, J = 17.3, 1.6 Hz, 1H), 5.41 (dd, J = 10.6, Hz, 1H), 4.95 – 4.88 (m, 2H), 4.22 (s, 3H), 4.16 (s, 3H); 13 C{1H}NMR (151 MHz, CDCl3) δ 152.8, 144.9, 142.4, 133.2, 130.4, 130.0, 128.7, 124.9, 124.2, 123.6, 122.9, 122.2, 120.8, 120.6, 119.3, 118.6, 117.8, 110.0, 69.7, 61.2, 61.1; HRMS (ESI) calculated for C21H18BrO3 ([M+H]+) m/z = 397.0439, found 397.0422. ASSOCIATED CONTENT Supporting Information 1 H and 13C NMR spectra for all new compounds, and crystallographic data, including CIFs. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This material is based upon work supported by the National Science Foundation under Grant Number (CHE-1654691). The authors are also grateful to Auburn University, the College of Sciences and Mathematics, and the Department of Chemistry and Biochemistry. We also thank Umicore for generous catalyst donations.

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